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当前位置: 香港综合肿瘤中心 > PD-1/PD-L1抑制剂资讯 > 免疫功能和免疫调节抗体靶向PD-1,PD-L1和CTLA-4的

免疫功能和免疫调节抗体靶向PD-1,PD-L1和CTLA-4的

文章出处:未知 责任编辑:admin 作者:admin 发表时间:2016-08-10 14:58

目的:为了评估dabrafenib和trametinib的免疫效果的体外和测试trametinib是否potentiates或拮抗体内免疫调节抗体的活性。

实验设计:dabrafenib和trametinib的免疫效果在人CD4(+)和CD8(+)从健康志愿者的T细胞进行了评价,在体内使用CT26小鼠模型人肿瘤细胞系组成的小组,和。

结果:Dabrafenib增强的pERK表达水平并没有抑制人CD4(+)或CD8 + T细胞的功能。Trametinib降低的pERK水平,并且导致T细胞增殖/表达的细胞因子和免疫调节基因的子集,这是上下文相关的局部/瞬态抑制。Trametinib影响部分加入dabrafenib抵消。Dabrafenib和trametinib BRAF中V600E / K和trametinib在诱导细胞凋亡标记物的BRAF野生型肿瘤细胞,上调HLA分子的表达,并下调某些免疫抑制因子,如PD-L1的,IL1,IL8,NT5E和VEGFA。在肿瘤细胞中PD-L1的表达在体外收购来抑制BRAF后电阻上调。

与免疫调节定位的PD-1 trametinib的组合,PD-L1的,或在一个CT26模型CTLA-4的比任何单一药剂更有效。trametinib与抗PD-1的结合增加肿瘤浸润的CD8(+)T细胞在CT26肿瘤。用抗PD-1抗体,然后由抗PD-1加trametinib相比trametinib引入随后trametinib加上抗PD-1抗体同时或分阶段顺序处理,定义为,证实优越功效。

结论:这些发现支持的协同潜力的靶向治疗dabrafenib和trametinib和免疫抗体。这样的联合治疗方案的临床探索正在进行。

 

Abstract

PURPOSE:

To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.

EXPERIMENTAL DESIGN:

Immune effects of dabrafenib and trametinib were evaluated in human CD4(+) and CD8(+) T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.

RESULTS:

Dabrafenib enhanced pERK expression levels and did not suppress human CD4(+) or CD8(+) T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD-1 increased tumor-infiltrating CD8(+) T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD-1 antibody, demonstrated superior efficacy compared with anti-PD-1 antibody followed by anti-PD-1 plus trametinib.

CONCLUSION:

These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way.


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